PO.TB07.01 · 肿瘤生物学
携带桥粒芯糖蛋白-2（Desmoglein-2）的癌症干细胞来源细胞外囊泡促进肺癌侵袭性
Desmoglein-2 carrying cancer stem cell-derived extracellular vesicles promote lung cancer aggressiveness
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
肺癌仍是全球癌症相关死亡的首要原因，其中非小细胞肺癌（NSCLC）约占所有病例的85%。尽管靶向治疗和免疫治疗取得了进展，但由于晚期检出和治疗耐药，NSCLC的总体生存率仍低于25%。癌症干细胞（CSC）是NSCLC内一个高度致瘤的亚群，驱动复发、转移和治疗失败。理解CSC促进NSCLC侵袭性的机制可能揭示新的诊断和治疗机会。CSC通过分泌细胞外囊泡（EV）——一种运输蛋白质、脂质和核酸并能影响受体细胞行为的膜结合纳米颗粒——建立细胞间通讯网络。我们此前的工作证明，与大宗癌细胞（BCC）相比，CSC分泌的EV显著更多，并在BCC中诱导增强的致瘤表型。然而，介导这些CSC驱动表型的EV蛋白货物及其促进的信号仍知之甚少。本研究旨在鉴定和表征促进NSCLC生长和转移的CSC来源EV蛋白货物。采用切向流过滤分离CSC来源和BCC来源的EV，并根据MISEV指南进行表征。进行质谱和通路分析以比较CSC来源和BCC来源EV的蛋白质组，随后进行体外和体内功能表征。我们的结果显示，EV表现出预期的形态学、生化和物理特性。通路分析显示，CSC来源的EV富集定位于外泌体并与代谢和细胞粘附相关的蛋白质。BCC与CSC来源EV的比较揭示桥粒芯糖蛋白-2（DSG2）是仅在CSC来源EV中检测到的蛋白质之一。shRNA介导的DSG2敲低在体外显著降低了侵袭、克隆扩增和转化生长，并在体内减少了肿瘤生长和转移。此外，DSG2功能完备的EV部分挽救了DSG2敲低对体内CSC肿瘤生长的影响。总之，这些发现将DSG2鉴定为一个关键的CSC特异性EV蛋白货物，促进增强的致瘤表型和NSCLC肿瘤生长。这项工作凸显了CSC来源EV蛋白作为NSCLC侵袭性介导因子以及生物标志物和治疗开发候选物的作用。
查看英文原文 English abstract
Lung cancer remains the leading cause of cancer-related deaths worldwide, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of all cases. Despite advances in targeted and immuno-therapies, overall survival for NSCLC remains below 25%, due to late-stage detection and therapeutic resistance. Cancer stem cells (CSCs), a highly tumorigenic subpopulation within NSCLC, drive relapse, metastasis, and treatment failure. Understanding the mechanisms by which CSCs promote the aggressiveness of NSCLC may reveal new diagnostic and therapeutic opportunities. CSCs establish an intercellular communication network through the secretion of extracellular vesicles (EVs), membrane-bound nanoparticles that transport proteins, lipids, and nucleic acids that can influence recipient cell behavior. Our previous work demonstrated that CSCs secrete significantly more EVs compared to bulk cancer cells (BCCs) and induce an enhanced tumorigenic phenotype in BCCs. However, the EV protein cargo that mediates these CSC-driven phenotypes and the signaling they promote remain poorly understood. This study aimed to identify and characterize CSC-derived EV protein cargo that contributes to NSCLC growth and metastasis. CSC- and BCC-derived EVs were isolated using tangential flow filtration and characterized according to MISEV guidelines. Mass spectrometry and pathway analysis were performed to compare the proteome of CSC- and BCC-derived EVs, followed by functional characterization in vitro and in vivo. Our results showed that EVs exhibited expected morphological, biochemical, and physical properties. Pathway analyses showed that CSC-derived EVs were enriched in proteins that localize to exosomes and associate with metabolism and cell adhesion. Comparison of BCC and CSC-derived EVs revealed Desmoglein-2 (DSG2) as one of the proteins exclusively detected in CSC-derived EVs. shRNA-mediated knockdown of DSG2 significantly reduced invasion, clonal expansion, and transformed growth in vitro and decreased tumor growth and metastasis in vivo . Furthermore, DSG2-competent EVs partially rescued the effects of DSG2 knockdown on CSC tumor growth in vivo . Together, these findings identify DSG2 as a key CSC-specific EV protein cargo that promotes an enhanced tumorigenic phenotype and NSCLC tumor growth. This work highlights the role of CSC-derived EV proteins as mediators of NSCLC aggressiveness and as candidates for biomarker and therapeutic development.
利益披露 Disclosure
P. Pandya, None..
A. Ahmed, None..
N. Murray, None..
D. S. Al-Qasrawi, None..
A. Y. Clarke, None..
R. Carris, None.